Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src.
Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src.
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DOI：
10.1186/1471-2121-10-84
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发表时间：
2009-11-30
期刊：
影响因子：
--
通讯作者：
Band H
中科院分区：
文献类型：
--
作者：
Chung BM;Raja SM;Clubb RJ;Tu C;George M;Band V;Band H
表皮生长因子受体（EGFR）控制着广泛的细胞过程，EGFR信号的改变与人类癌症有关。在非小细胞肺癌（NSCLC）中发现的EGFR激酶结构域突变体具有组成性活性，这是通过激活下游途径进行细胞转化的关键特征。EGFR的内吞运输是一个主要的调节机制，因为配体诱导的溶酶体降解导致信号终止。虽然许多研究已经检查了突变EGFR信号，但突变EGFR在NSCLC环境中的内吞运输仍然不太清楚。这项研究表明，突变型egfr在NSCLC细胞系中组成性内吞噬，这表明它们与早期/循环内体标记物转铁蛋白和晚期内体/溶酶体标记物LAMP1共定位。值得注意的是，突变型EGFR，而不是野生型EGFR，在用内吞噬再循环抑制剂莫能菌素处理细胞后，表现出核周积累和与再循环内体标记（如Rab11和EHD1）共定位，这表明突变型EGFR优先通过内吞噬再循环室运输。重要的是，莫能菌素处理增强了突变体EGFR与Src的关联和共定位，表明通过内噬循环室的异常转运促进了突变体EGFR-Src的关联。本研究的发现表明，突变型egfr会异常地进入内吞循环室，这使得突变型egfr能够优先与Src相互作用，Src是egfr介导的肿瘤发生的关键伙伴。
Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and altered EGFR signaling contributes to human cancer. EGFR kinase domain mutants found in non-small cell lung cancer (NSCLC) are constitutively active, a trait critical for cell transformation through activation of downstream pathways. Endocytic trafficking of EGFR is a major regulatory mechanism as ligand-induced lysosomal degradation results in termination of signaling. While numerous studies have examined mutant EGFR signaling, the endocytic traffic of mutant EGFR within the NSCLC milieu remains less clear. This study shows that mutant EGFRs in NSCLC cell lines are constitutively endocytosed as shown by their colocalization with the early/recycling endosomal marker transferrin and the late endosomal/lysosomal marker LAMP1. Notably, mutant EGFRs, but not the wild-type EGFR, show a perinuclear accumulation and colocalization with recycling endosomal markers such as Rab11 and EHD1 upon treatment of cells with endocytic recycling inhibitor monensin, suggesting that mutant EGFRs preferentially traffic through the endocytic recycling compartments. Importantly, monensin treatment enhanced the mutant EGFR association and colocalization with Src, indicating that aberrant transit through the endocytic recycling compartment promotes mutant EGFR-Src association. The findings presented in this study show that mutant EGFRs undergo aberrant traffic into the endocytic recycling compartment which allows mutant EGFRs to engage in a preferential interaction with Src, a critical partner for EGFR-mediated oncogenesis.
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